1. Field of the Invention
The present invention relates generally to the field of polymer chemistry and drug delivery. More particularly, it concerns hydrogel polymers that may be used for the oral delivery of therapeutic compounds.
2. Description of Related Art
Environmentally-responsive hydrogels, or hydrophilic, crosslinked polymer networks that undergo physicochemical changes in response to one or more environmental stimuli, offer the specificity of highly tunable materials combined with excellent biocompatibility (Peppas et al., 2006; Hoffman, 1991; Qiu and Park, 2001; Caldorera-Moore and Peppas, 2009). As the next generation of biomaterials, these “intelligent” networks are able to respond to or mimic biological environments and processes such as vascularization (Bae et al., 2012; Phelps et al., 2009), tumor physiology (Lin et al., 2013; Liechty et al., 2012), endosomal compartments (Wong et al., 2014; Forbes and Peppas, 2014; Liang et al., 2014), or the extracellular matrix (Guvendiren et al., 2013; Kirschner et al., 2013). This capability could be instrumental in achieving various biomedical advances, including tissue regeneration and controlled delivery of biological therapeutics (Knipe et al., 2014a; Holzapfel et al., 2013).
Some hydrogels with pH-responsive behavior may be used as hydrogel systems for drug delivery applications (Peppas et al., 2000). Polyanionic hydrogels such as poly(methacrylic acid) (PMAA) exhibit complexation via hydrogen bonding at low pH conditions, such as that of gastric fluid, and undergo increased swelling due to ionization of the carboxylic groups at neutral pH conditions, such as that of the intestine (Kost et al., 2012). Thus, PMAA copolymers have been utilized as oral drug delivery carriers or coatings for their ability to protect a loaded therapeutic from denaturation and enzymatic degradation as it travels through gastric conditions yet swell and release the therapeutic at the site of absorption in the small intestine (Torres-Lugo et al., 2002; Torres Lugo et al., 1999; Knipe et al., 2014; Lowman et al., 1999; Carr et al., 2009; Carr and Peppas., 2010).
Biodegradation is another possible environmental response of hydrogels designed for drug delivery applications (Knipe et al., 2014; Hu et al., 2012). Polymers that degrade by hydrolysis, such as polyanhydrides (Torres et al., 2007; Lopac et al., 2009), poly(orthoesters) (Hoffman, 1991; Thombre et al., 1985), poly(caprolactone), and poly(lactic acid) and poly(glycolic acid) (Lao et al., 2008; Anderson et al., 2012) have been used for drug delivery.
Oral delivery of siRNA might be used for treating diseases of the gastrointestinal (GI) tract, such as inflammatory bowel diseases, and intestinal absorption could offer a route to systemic delivery. However, there are many extracellular and intracellular barriers to oral siRNA delivery such as proteolytic degradation (Fattal et al., 2008), harsh pH environments (Bouchie et al., 2012), and the necessity to achieve intracellular delivery and endosomal escape while maintaining the integrity of the siRNA (Whitehead et al., 2009; Schiffelers et al., 2003), making successful oral delivery of siRNA a daunting task. The current strategies for oral delivery of siRNA to the intestine are relatively few in number, and they employ approaches that are only effective in a limited capacity. Clearly there exists a need for improved methods for oral delivery of therapeutic nucleotides
Despite improvements in oral delivery of therapeutic proteins using hydrogel polymers, there nonetheless exists a significant need for improved control over release of the therapeutic in the small intestine from the hydrogel. Additionally, there remains a need for hydrogel polymers that are optimized for delivery of particular therapeutics.